This project is designed to provide a better understanding of the mechanisms by which gonadal steroids can influence neuronal survival and function in the adult and aging brain. In particular, we are interested in effects of estrogen on specific basal forebrain cholinergic neurons, and in the possible effects of estrogen replacement therapy on neuronal survival and function in both young and aged women. The long-term objective is to understand how prolonged exposure to gonadal steroids may contribute to neuronal loss and functional decline with age and to acquire information which can ultimately be used to develop new therapeutic approaches for treating functional loss associated with neural injury and aging. Our studies will focus on gonadal steroid effects which influence the functioning of basal forebrain cholinergic neurons. Note that these neurons play an important role in leaning and memory processes and their loss is thought to contribute to the cognitive decline associated with normal aging as well as with specific neurodegenerative diseases. Nerve growth factor (NGF) is a target-derived trophic factor which can influence the survival and function of these basal forebrain cholinergic neurons. In situ hybridization and immunocytochemical techniques will be used to examine gonadal steroid effects on NGF, NGF receptors, and choline acetyltransferase (ChAT) gene expression within the hippocampal formation, medial septum, diagonal band of Broca, and nucleus basalis of Meynert on a cell-by-cell basis. Biochemical analysis will also be used to examine effects on regional levels of ChAT activity. The experiments described derive from recent studies showing estrogenic effects on NGF, NGF receptor, and ChAT expression in the adult female hippocampal formation and basal forebrain. Major questions which will be addressed include: l. Are the effects of estrogen on NGF, NGF receptor, and ChAT expression which have been observed in females also observed in males? 2. Do the levels of NGF, NGF receptor, or ChAT mRNA change in the rat hippocampal formation and basal forebrain as a function of the normal estrus cycle and, if so, are those changes analogous to those produced with different levels of estrogen replacement? 3. Are the effects of estrogen treatment on NGF and NGF receptor expression the result of estrogen regulation of cholinergic activity in the basal forebrain and hippocampal formation? 4. Does estrogen replacement have the same effects on NGF, NGF receptor, and ChAT expression in the brains of aged animals as it does in young adults? 5. Does cyclic estrogen treatment or estrogen treatment combined with progesterone have that same effects on NGF, NGF receptor, and ChAT expression as does continuous estrogen treatment? 6. Can estrogen enhance the regeneration of and/or decrease the loss of basal forebrain cholinergic neurons following injury comparable to the effects of testosterone on injured facial and hypoglossal neurons?